Glaucoma is a leading cause of blindness. Elevated intraocular pressure (IOP) is a major risk factor for glaucoma. Our goal is to identify and characterize genetic factors that contribute to elevated IOP and glaucoma. Specifically, we are using the mouse as a model system to conduct a phenotype driven mutagenesis screen to identify novel mechanisms and pathways involved in glaucoma pathogenesis. The power of phenotype driven mutagenesis screen is that there is no requisite a priori information for factors or pathways involved. Since little is currently known about IOP homeostasis, this method for identification of new genetic factors is ideal. We propose that in the time of this grant we will identify approximately 10 new glaucoma related mutations. This method has already provided us with one new locus (Eel) for primary congenital glaucoma that we propose to clone and a second enlarged eye mutant (Ee3) that we will characterize and fine map. A feature of our phenotype-driven screen is enrichment for mutation detection on mouse chromosome 5, in a region of conserved synteny to human chromosome 7q36. This region contains 2 human glaucoma loci for which the genetic cause is unknown. While we are able to enrich for this region of considerable interest, our method does not impede the likelihood of identifying mutations elsewhere in the genome. Therefore, mutations contributing to IOP and will be mapped and prioritized based on similarity to human glaucomatous phenotypes and known human glaucoma map positions. We predict that using the power of a phenotype driven mutagenesis screen in parallel with our unique tools to examine ocular phenotypes we will be able to identify and characterize new genetic factors that contribute to elevated IOP and advance understanding of glaucoma.